ocular therapeutics · ocular drug delivery ∗ formulation considerations for ocular drugs ∗...

Ocular Therapeutics

Brian C. Gilger, DVM, MS, Dipl. ACVO, Dipl. ABTProfessor of Ophthalmology

bgilger@ncsu.edu

2018

Practice of Ophthalmology

1. Selecting the correct pharmacologic agent

2. Achieve appropriate dose at the target ocular tissue

3. Select delivery method that does not damage healthy tissue

(Weiner & Gilger, Ocular Drug Delivery, Veterinary Ophthalmology2010).

Overview

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∗ Three important aspects1. Duration of drug delivery needed2. Intended tissue target3. Owner or patient compliance

When considering drug delivery methods

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Months After Initiating Medications

Chronic Therapeutics

Medication adherence - how well a patient takes (or is given) the prescribed medication according to the recommended dosing schedule

Medication persistence - whether or not a patient stops taking medication completely

Muir Arch Ophthalmol. 2011 Feb; 129(2): 243–245.

Challenges to Ocular Drug Delivery

∗ Highly sensitive ocular tissues

∗ Tissue barriers to drug penetration:

∗ Lipophilic corneal epithelium

∗ Hydrophilic corneal and scleral stroma

∗ Conjunctival lymphatics

∗ Choroidal vasculature

∗ Blood-ocular barriers.

Overview

Ocular Drug Delivery

∗ Formulation considerations for ocular drugs

∗ Review pharmacology of topically applied drugs∗ Corneal penetration

∗ Practical methods to increase drug penetration

∗ Alternative methods∗ Drug devices, injections

∗ Ocular formulations∗ Solutions

∗ Adv: dose uniformity, ease of manufacturability and often provides better bioavailability.

∗ Disadv: rapid clearance and a short precorneal residence time after instillation

∗ Suspensions∗ Coarse dispersion of insoluble solid particles of a drug ∗ Adv: provide higher bioavailability by prolonging

residence time of formulations in precorneal area ∗ Disadv: The particle size 95 % <10 um to avoid foreign

body sensation

General Features of Ocular Drug Delivery

∗ Ocular formulations∗ Ointments

∗ Sterile semisolid ∗ Typically involves a combination of mineral oil and white

petrolatum.∗ Adv: better product stability; better bioavailability due to

longer residence time of the formulation, and dilution effect due to tear is marginal and low nasolacrimal clearance

∗ Disadv: Messy, difficult to apply? Blurred vision?

General Features of Ocular Drug Delivery

Ocular Drug Delivery

∗ Formulation considerations for ocular drugs

∗ Review pharmacology of topically applied drugs∗ Corneal penetration

∗ Practical methods to increase drug penetration

∗ Alternative methods∗ Drug devices, injections

Topical Ocular Medications

§ The main route of topical drug entry to the anterior chamber is penetration through the cornea.

§ Peak concentration in aqueous humor is typically 20 to 60 minutes.

Topical

§ In general, the amount of drug penetrating the cornea is linearly related to its concentration in the tear film

Pharmacokinetics

Topical Ocular Medications

∗ Commercially available topical medications dispense a range from 25.1 to 70 μL (average drop size of 39 μL).

∗ Tear volume ∗ Human= 7–9 μL (turnover rate of 0.5–2.2 μL/min).

∗ Palpebral fissure “holds” 25-30 uL∗ Complete turnover in 10 min

∗ Horse = 230 uL (rate 33 uL/min)

∗ Application of topical drop causes increase in tear volume and rapid reflex blinking.

∗ Remainder is drained into systemic circulation via nasolacrimal duct or overflow onto face.

Topical Ocular Medications

§ Because of these properties, only 7 to 10% of a topical dose of medication ever reaches the anterior chamber.

§ The remainder exits with the tear film through the nasolacrimal system, is deposited on the eyelids, or metabolized by enzymes in the tears and surface tissue.

§ Systemic absorption of some drugs can be significant.

Topical Ocular Medications

Properties of Corneal Drug Penetration

§ The cornea is essentially a multilayered sandwich § fat (epithelium)§ water (stroma)§ fat (endothelium)

Properties of Corneal Drug Penetration

§ The epithelium is the major barrier to absorption, especially for hydrophilic medications.

Properties of Corneal Drug Penetration

§ The corneal stroma is a major barrier for lipophillicdrugs.

Ocular Drug Delivery

∗ Formulation considerations for ocular drugs

∗ Review pharmacology of topically applied drugs∗ Corneal penetration

∗ Practical methods to increase drug penetration

∗ Alternative methods∗ Drug devices, injections

§ Prolong the topical contact time of the drug. § vehicles with increased corneal contact time

§ gels, ointments, emulsions, or biodegradable inserts§ Increase viscosity § Instill drug in a contact lens (30-70% water)

é viscosity = é retention =

é residence time =é amount of drug absorption

Practical methods to increase topical drug penetration

Topical Route of Administration

§ Ophthalmic solutions / suspensions§ If desire a higher conc. of drug in eye - instead of giving more

drops at one time:

§ Increase frequency of administration

§ (wait 5 minutes between drops)

§ Use higher concentration of drug

§ (watch for toxicity / irritation)

§ Improve ocular penetration

§ (remove epithelium)

Topical Ocular Administration

§ Prolong the topical contact time of the drug. § vehicles with increased corneal contact time

§ gels, ointments, or biodegradable inserts.

§ Increase viscosity § Instill drug in a contact lens (30-70% water)

§ Alter the epithelium § Damaging the epithelium can reduce the barrier properties

of the epithelium.

Methods to increase topical drug penetration

Methods to increase topical drug penetration

§ Alter the epithelium § Damaging the

epithelium§ Corneal scraping§ Epithelial debridement§ Certain topical medications

contain preservatives or surfactants that increase penetration§ E.g., Benzalkonium chloride

Methods to increase topical drug penetration

•Choose a medication that will stay on the cornea

•Improve penetration by altering epithelium

•Bypass barriers

•Subconj injection

•Intraocular injection

•Ocular implants

Topical Drug DeliveryImproving penetraiton

Dedicated subpalpebral \ nasolacrimal lavage system

Topical Drug Delivery

Dedicated Lavage System...

∗ Overcome compliance problems∗ ?High drug wastage in dead space – cost

∗ Subpalpebral lavage- easy placement, well tolerated- dorsal location → better drug bioavailability

∗ Nasolacrimal lavage system- problems with retaining in-situ- increased drug retention time is a potential advantage- Rarely done

Route of Administration of Ophthalmic Medications

∗ Subconjunctival Injections∗ Bypass ocular barriers!∗ Great ocular penetration∗ Most aqueous soluble IV meds well

tolerated∗ Can give up to 0.25 cc∗ Use with caution, esp steroids

∗ Once injected - cannot reverse∗ Only for those animals that cannot

be treated frequently

Subconjunctival injections

Route of Administration of Ophthalmic Medications

∗ Intraocular injections∗ Risky due to toxicity of many

drugs∗ Gentocin used to destroy eye

in chronic glaucoma∗ 20 to 35 mg of gentocin (.25-.30

cc of 100mg/ml)

24 hours post injection 10 mg Rapamycin

Ocular Drug Delivery

∗ Formulation considerations for ocular drugs

∗ Review pharmacology of topically applied drugs∗ Corneal penetration

∗ Practical methods to increase drug penetration

∗ Alternative methods∗ Drug devices, injections

Sustained Drug Delivery Devices

§ Sustained release of medication

§ To ocular surface and intraocularly

§ Canine KCS, equine IMMK

General Features of Ocular Drug Delivery

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Therapeutic

Toxicity

Sub-therapeutic Repeat

Dose

Sustained Drug Delivery Devices

Matrix-Reservoir Implant

6 MM

12 MG, 4.5 MM CSA PELLET IN 15% CSA PVA

Projected release duration: 3.18 years

Sustained Release Drug Delivery

• Equine uveitis• Canine KCS• Effective delivery of

medications to the suprachoroidal and episcleral space is feasible

∗ Ozurdex: dexamethasone/PLGA

∗ Retisert : Flucinolone

∗ Envisia (ENV 515XR)∗ Travaprost

∗ Bimatoprost SR (Allergan)

Commercially available sustained ocular drug delivery devices

Advances in ocular drug delivery

∗ Thermosensitive, biocompatible, hydrogels∗ Advanced implant technologies∗ Mesenchymal stem cells∗ Would healing and immunomodulation

∗ Gene therapy∗ Gene replacement∗ Gene addition studies

∗ Iontophoresis

Keratoconjunctivitis sicca (dry eye)

∗ Forsight Rings∗ Current clinical trial

ongoing with canine KCS (NC State)∗ Well tolerated∗ Great retention∗ Results are pending

https://www.allergan.com/

Ocular Drug Delivery

∗ Formulation considerations for ocular drugs

∗ Review pharmacology of topically applied drugs∗ Corneal penetration

∗ Practical methods to increase drug penetration

∗ Alternative methods∗ Drug devices, injections

Thank you

The Gilger Lab (NCSU)- Jacklyn Salmon- Amanda Davis- Megan Cullen- Allison Blanchard- Elizabeth Crabtree

Hirsch Lab (UNC)

NCSU Clinical OphthalmologyService

• Active Patents– AAV-HLA-G therapy for the eye (with Matt Hirsch, NC State University, UNC Chapel Hill)– Ocular injection needle device (with Samir Patel, Vladimir Zarnitsyn, NC State University)– Anti-fungals (With NCSU CIFR) (invention disclosed)

• Sponsored Research– Allergan Inc, Forsight ring CsAclinical trial– Fortress Biosciences (Tamid, Inc). - corneal transplant rejection

• Company affiliations – co-founder– Bedrock Therapeutics, Inc., Gene and cell therapy applications– Theia Biotherapeutics, Inc., Ocular drug delivery

• Consultant– Powered Research, Ophthalmic CRO, Research Triangle Park, NC

Conflicts of interest - Active

Questions?